Opioids. acetylcholine, norepinephrine and kappa antagonists

[Nova]

Opioids have always had a bizarre effect on me and have always facinated me with their mental effects (not so much the analgesic effects). Certain opiates give me an almost amphetamine like energy, almost like a sort of restlessness, along with contentness or 'normal' feeling. An optimal dose of oxycodone will have me cleaning my place almost like im tweaked out; i'm motivated to do all the things I need to or should be doing, traits that I naturally lack. Others have reported that they have a similar reaction to certain opioids. So I was wondering what could be the cause of a seemingly couterintuitive reaction when I came across this journal article.

It basically says opioids were observed to increase the levels of norepinephrine and acetylcholine in sheep (measured in their spine). The more I thought about it, it made sense that this could be an alternate mode of action through which opioids induce euphoria/motivation. Acetylcholine

In the central nervous system, ACh has a variety of effects as a neuromodulator, e.g., for plasticity and excitability. Other effects are arousal and reward.

And nicotine, an acetylcholine agonist

By binding to nicotinic acetylcholine receptors, nicotine increases the levels of several neurotransmitters - acting as a sort of "volume control". It is thought that the increased levels of dopamine in the reward circuits of the brain is what is responsible for the euphoria/pleasure, relaxation and eventual addiction caused by nicotine consumption.

Further readings here dealing with ACh effect on reducing stress

Norepinephine is also closely tied to dopamine and obviously has a role in anti depressants in current medicine. NRI (norepiniphrin reuptake inhibitors- like atomoxetine- strattera) users report a calm relaxed alertness. More ties between opioids and NE are discussed here.

Summary: The reason I write all this is because it is relatively new to me and I was wondering if anyone had any other thoughts on this/corrections to what i wrote. The odd motivated almost speedy aspect of chemicals like oxycodone, oxymorphone, and buprenorphine are interesting to me and maybe someone else has a better theory/evidence as to while they produce these effects? Also i'm interested in the mood enhancing effects of opioids and their possible use as anti depressants/anti anxiety and wanted to look into it more than the mesolimbic pathway and dopamine which seem to have problems with things like addiction and tolerance. I'm also very interested in kapa antagonists such as nor-binaltorphimine and JDTic that opioids.com has a bunch of articles on. I have a hunch these highly selective kappa antagonists might work through these 'periphery' routes and bypass the negative of today's common opiates. Their length of duration is also astonishing (up to 133 days in nor-bin). But these k antagonists are still very new and not much research is done on them yet. Any additional info/insight into their mode of action and any theoretical positive psychiatric effects would be very interesting and appreciated.

 

[Tchort]

Doesn't sound like a bizarre effect. That is a typical reaction to many opioids, specifically the ones you list (Oxycodone, Buprenorphine). Stimulation is standard, I've always found it impossible to sleep after using Oxycodone recreationally at night.

Other opioids produce a similar effect in a lot of people. Not to the same extent, but notoriously sedating opioids can have a similar motivating/energetic quality as well- Heroin, Methadone, etc.

 

[Easko]

Doesn't sound strange. I think it's pretty standard. Hydro even has that effect on me. Morphine too, and it's not even particularly sedating.

 

[Tsukasa]

The alertness, motivation, warm euphoria is from the dopamine release. This is fact.

Theirs also release of histamine and vasopressin (in mu agonists, opposite in k-opioids), which also affect wakefullness, increase cognitive function, itching, and water retention.

The actual opioid effect is the respiratory depression, miosis, sedation, etc..

 

[Hammilton]

The alertness, motivation, warm euphoria is from the dopamine release. This is fact.

Theirs also release of histamine and vasopressin (in mu agonists, opposite in k-opioids), which also affect wakefullness, increase cognitive function, itching, and water retention.

The actual opioid effect is the respiratory depression, miosis, sedation, etc..

I don't know about that. I can't find a study that says DA antagonists block the reinforcing effects of mu1 agonists.

 

[Tsukasa]

^ You don't need studies to know that. Just take some levodopa and see how you feel and compare it to opioids. Also notice how you feel after it wears off. The warm euphoria goes away and you feel tired, just left with the sedation from the actual opioid effects. I'm sure if you search hard enough you'll find some studies. It's also fact that endogenous mu-opioid agonists like beta-endorphin dis-inhibit dopamine pathways.

 

[negrogesic]

I think the wakefulness promoting qualities of some opioids (especially those that are thebaine derived) are more likely to be NE mediated than DA mediated. This may also contribute to the anxiogenic qualities of the codones.

Plus, NE has a closer association with wakefulness than dopamine. Yes, dopamine does play a role in the reinforcing properties of opioids (check out: http://www.sciencedirect.com/scienc...serid=10&md5=9be06bdec33680ded7349282e3d259a6 ), but it may not be main driving force behind the CNS stimulation.

BACKGROUND: Opioids produce analgesia by direct effects as well as by activating neural pathways that release nonopioid transmitters. This study tested whether systematically administered opioids activate descending spinal noradrenergic and cholinergic pathways. METHODS: The effect of intravenous morphine on cerebrospinal fluid and dorsal horn microdialysate concentrations of norepinephrine and acetylcholine was examined in 20 sheep. Animals received either intravenous morphine or fentanyl alone, or morphine plus intravenous naloxone or intrathecal idazoxan. RESULTS: Intravenous morphine (0, 0.5, 1 mg/kg, intravenous) produced dose-dependent increases in cerebrospinal fluid norepinephrine and acetylcholine, but not epinephrine or dopamine. Morphine's effect was blocked by intravenous naloxone and by intrathecal idazoxan. In microdialysis experiments, intravenous morphine increased the concentration of norepinephrine and acetylcholine, but not epinephrine or dopamine, in the dorsal horn. In contrast, intravenous morphine exerted no effect on any of these monoamines in the ventral horn. Intravenous naloxone and cervical cord transection each blocked morphine's effect on dorsal horn norepinephrine. CONCLUSIONS: These results support functional studies that indicate that systematically administered opioids cause spinal norepinephrine and acetylcholine release by a naloxone-sensitive mechanism. Idazoxan blockade of morphine's effects on cerebrospinal fluid norepinephrine was unexpected, and suggests that both norepinephrine and acetylcholine release in the spinal cord may be regulated by alpha 2-adrenoceptors. Microdialysis experiments suggest increased norepinephrine and acetylcholine levels in cerebrospinal fluid resulted from intravenous morphine-induced activation of bulbospinal pathways.
http://www.mdconsult.com/das/citati...urce=MI&sp=971300&sid=0/N/971300/1.html?issn=

The most stimulating opioids in my mind are: oxycodone/morphone, hydrocodone, meperidine (this one doesn't really count due to direct reuptake inhibition), and methadone (can be both stimulating and sedating). Fentanyl can also have stimulating properties after a tolerance is developed.

Morphine is almost always sedating (more so than heroin), and I found levorphanol to be quite sedating...

 

[Tsukasa]

^ The method of administration may explain the release of noradrenaline and acetylcholine, since even opioid antagonist give and adrenaline rush when injected. Though if you can find studies that show the same results when opioids are taken orally, then that may explain why some opioids are more speedy than others (atypical opioids aside), yet provide the same level of euphoria. Norepinephrine is not know to cause euphoria, even though it has an anti-depressant effect in some individuals. Theirs also the example of demerol, which has speedy qualities yet actually antagonizes acetylcholine receptors.

Theirs no doubt in my mind that dopamine is released indirectly with mu-opioid receptor agonists. Dopamine also plays a role in ability to sleep soundly, which may explain the waking dreams or "nodding" where you're half asleep and don't even feel the urge to change positions or wake up when confronted with disturbing stimuli in your vivid imagination/dreams. Then theirs also that effect on motivation where you feel the urge to do stuff like clean your house, do homework, etc., and the increase in thinking, planning, problem solving, creative, and psychic ability.

Dopamine also plays a role in immune function. The phrase "laughter is the best medicine" comes from the release of endorphin with laughter, and the consequent release in dopamine, which increases our immune systems. Which is why therapies like the laughing rooms are so effective in helping to cure illness'

 

[Hammilton]

^ You don't need studies to know that.

I'm sorry, did you forget what forum you're in? Perhaps in OD it's common to make assertions without any need or desire for backing, but here, dealing in facts, scientific validation is needed when you make claims.

Otherwise, like everything else that's untested, it means nothing. That's how science works. You're actually saying that we should take things as fact that haven't been tested and proven. We already have people that do this, they're Tom Cruise and Pope Benedict.

 

[Tsukasa]

^ Fine, here are the studies you were looking for.

http://opioids.com/dopamine/dopamine.html

"e have previously reported that mesolimbic dopamine (DA) substrates are critically involved in the rewarding effects of opiates only during states of opiate-dependence and withdrawal. However, in previously drug-naive animals, opiate reward is mediated through a DA-independent neural system. In the present study, we report that bilateral microinjections of a DA receptor antagonist, alpha-flupenthixol (0.3-3 microg/0.5 microl) into the nucleus accumbens (NAc), blocks morphine reward (10 mg/kg, i.p.) in opiate-withdrawn animals, but not in opiate-naive animals, suggesting that accumbal dopamine receptors are required for opiate reward signaling in drug-deprived motivational states. Next, the role of dopamine was examined in the development of opiate dependence and somatic withdrawal, and expression of withdrawal aversions. Pretreatment with alpha-flupenthixol (0.8 mg/kg, i.p.) before morphine injections during the development of opiate dependence did not effect expression of withdrawal aversions or the expression of somatic withdrawal. We have previously reported that pretreatment with a dopamine receptor antagonist, alpha-flupenthixol, blocks the aversive effects of opiate withdrawal. We now report that pretreatment with a direct dopamine receptor agonist, apomorphine (1.0-5.0 mg/kg, i.p.) before conditioning in a state of withdrawal, also blocks the aversive effects of opiate withdrawal. We propose that the aversive motivational effects of opiate withdrawal may be mediated by a specific dopaminergic neuronal signal."


http://www.macalester.edu/psychology/whathap/UBNRP/Dopamine/opioids.html

"DiChiara and North (1992) propose that opioids hyperpolarize GABA-interneurons in the VTA, which reduces the inhibition on dopaminergic neurons projecting to the NA. Consequently, dopaminergic neurons are overstimulated, which causes an increase in reinforcement associated with addiction. While the hypothesis is sound, it has not been conclusively proven. Preliminary evidence does support the contentions of DiChiara and North. A recent study found that opioid administration reduces GABA mRNA, which is the template and controller of GABA production (Mavridis and Besson, 1999)."


http://en.wikipedia.org/wiki/Endorphin

"Beta-endorphin has the highest affinity for the μ1-opioid receptor, slightly lower affinity for the μ2- and δ-opioid receptors and low affinity for the κ1-opioid receptors. μ-receptors are the main receptor through which morphine acts. Classically, μ-receptors are presynaptic, and inhibit neurotransmitter release; through this mechanism, they inhibit the release of the inhibitory neurotransmitter GABA, and disinhibit the dopamine pathways, causing more dopamine to be released. By hijacking this process, exogenous opioids cause inappropriate dopamine release, and lead to aberrant synaptic plasticity, which causes addiction. Opioid receptors have many other and more important roles in the brain and periphery however, modulating pain, cardiac, gastric and vascular function as well as possibly panic and satiation, and receptors are often found at postsynaptic locations as well as presynaptically."

Next time actually search for them you fucking nerd. Don't just say you can't find them for the sake of arguing.

Also, what else could cause the nausea from opioids even when injected? DA and 5-HT are mostly responsible for nausea, and their are no studies to my knowledge showing opioids have any effect on 5-HT3 receptors, which stimulate emesis. Do you also think the ego-hardening, self confidence and optimism is from norepinephrine or acetylcholine which play little to no role in promoting them?

 

[thelonegunman]

The odd motivated almost speedy aspect of chemicals like oxycodone, oxymorphone, and buprenorphine are interesting to me and maybe someone else has a better theory/evidence as to while they produce these effects? Also i'm interested in the mood enhancing effects of opioids and their possible use as anti depressants/anti anxiety and wanted to look into it more than the mesolimbic pathway and dopamine which seem to have problems with things like addiction and tolerance. .

I don't have much to add except that I have spent the last ten years just kind of knowing the same thing without describing it. On non-intoxicating levels I am who I want to be, all the normal things you describe.
No anti depressant has ever worked as well as some forms of opiates i've taken, in normal doses, and feel human. Unfortunately, I always have to stop because of tolerance and addiction.
I am now trying low dose bupe for an anti-d strategy. Wondering if im still strung out or just normal and happy, taking like 2 mg every morning, maybe 2 at night.

Any info is appreciated.

 

[thelonegunman]

^ You don't need studies to know that. Just take some levodopa and see how you feel and compare it to opioids. Also notice how you feel after it wears off. The warm euphoria goes away and you feel tired, just left with the sedation from the actual opioid effects. I'm sure if you search hard enough you'll find some studies. It's also fact that endogenous mu-opioid agonists like beta-endorphin dis-inhibit dopamine pathways.

I disagree with the other posters arguing you on this point. Yes, studies are needed to be read, but I've taken the drugs and others and can give you the field test report from actual experience. yeah, it makes me anti-depressed, for sure, even at non intoxicating levels. I don't need a study to tell me this. So I agree with this poster

 

[Hammilton]

I disagree with the other posters arguing you on this point. Yes, studies are needed to be read, but I've taken the drugs and others and can give you the field test report from actual experience. yeah, it makes me anti-depressed, for sure, even at non intoxicating levels. I don't need a study to tell me this. So I agree with this poster

Again, you're an idiot. You're forming opinions on the mechanism of a drug based upon the fact that it leaves you feeling less depressed?

Sorry: that's impossible. There are all sorts of different routes of alleviating depression.

Next time actually search for them you fucking nerd. Don't just say you can't find them for the sake of arguing.

The first study you supply is only relevant in animals with previous dependency. This puts an awfully large constraint on your claims that certain subjective effects are the result of DA release.

The second paper you cite refers to their hypothesis, not to research that proves their claims. This sort of gets back to the whole needing to prove things first, thing, no?

Finally, that section of the wiki-entry you 'cite' (LOL) is entirely unsourced, and the first study you supply seems to disprove that hypothesis. Were aberrant DA release actually responsible for addiction, you would be without reinforcing effects in antagonist treated animals.

So, based on what you have provided, you might be able to say that perhaps DA release takes on some special importance in the reinforcing effects of previously dependent animals, but obviously not in first creating dependence.


Yes, quite obviously other neurotransmitters and NT systems are involved in the effects of opioid subjective effects, to what extent or what effects are caused by what, canot be said as you're claiming to be do.

Don't just say you can't find them for the sake of arguing.

You weren't able to find them, so... huh... You might want to carefully read the things you think prove what you claim they do.

 

[Tsukasa]

Those studies OP linked us to is only valid in sheep. In humans, their was only an observation made. So linking to studies only with animals such as rats which are genetically very similar to humans is no less valid.

http://www.jneurosci.org/cgi/content/abstract/12/2/483

Another study that shows opioids excite dopamine cells through dis-inhibition. SO DA does take a big role in the positive reinforcement of opioids. However, I did not say it has much to do with dependence.

 

[pofacedhoe]

so when a drug that is addictive enters the body dopamine is not the reason why more of that drug gets put in by the owner of the body?

 

[Hammilton]

Another study that shows opioids excite dopamine cells through dis-inhibition. SO DA does take a big role in the positive reinforcement of opioids. However, I did not say it has much to do with dependence.

No, the study you cited showed that they do something. It doesn't say anything about the reinforcing effects. Or rather, it makes a hypothesis based upon the in vitro findings. I think you're confused about what in vivo and in vitro studies are actually capable of showing. In vivo, the study you initial provided showed that opioids ARE reinforcing regardless of any DA disinhibition. The in vitro study you provide posits that the reinforcing effects are due to DA inhibition, but as the study you provided initially shows, that's not the case.


Just so you remember what you claimed (without any supporting evidence):

The alertness, motivation, warm euphoria is from the dopamine release. This is fact.

Nothing you've provided is even a little bit relevant in proving this 'fact.' Hell, you've not even shown a study that shows that opioids aren't reinforcing when DA receptors are blocked (except for a small subpopulation of previously dependent individuals).

 

[Hammilton]

so when a drug that is addictive enters the body dopamine is not the reason why more of that drug gets put in by the owner of the body?

I wouldn't say that: it's at least part of the equation though.

 

[theWorldWithin]

Hammilton I agree with what you are getting at on the lack of studies, but what then do you hypothesize is responsible for opiates reinforcing properties? I had always also assumed it was due to DA release but now I am not so sure, but I am at a loss for an alternate explanation. Can we draw any valid parallels between opiate reinforcement and that of exercise addiction? Is it plausible that opiates target some other unknown receptor system that may be responsible for the reinforcing properties? I think it is unlikely but I'm not sure.

Despite the lack of any conclusive studies the DA hypothesis would seem to be the most sound at this time just for lack of other viable alternatives that I am aware of.

 

[Hammilton]

Is it plausible that opiates target some other unknown receptor system that may be responsible for the reinforcing properties? I think it is unlikely but I'm not sure.

Why would there need to be another receptor system? What's wrong with the opioid receptor system itself? There are opioid receptors expressed in the nucleus accumbens, so, I dunno.

but what then do you hypothesize is responsible for opiates reinforcing properties? I had always also assumed it was due to DA release but now I am not so sure

I'd bet it's primarily DA release. However, stimulating the MOR without any downstream DA effects is reinforcing, though not in previously dependent rats. I would have thought that they'd be reinforcing no matter what in previously dependent rats- that's surprising. I think it indicates that tolerance to the reinforcing effects of MOR stimulation alone develops, but thanks to DA release, it doesn't matter.

There needs to be more research, of course. The big question that comes to mind is if we added a group of rats with increasing levels of exposure (and presumably, tolerance), and at what point the DA antagonism prevents it from being reinforcing.

 

[thelonegunman]

Again, you're an idiot. You're forming opinions on the mechanism of a drug based upon the fact that it leaves you feeling less depressed?

Sorry: that's impossible. There are all sorts of different routes of alleviating depression.



No, you're a moron, because I've taken them long enough to know they work that way, for me, so i don't need a study. but, read some, you might like them.